Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: An fMRI study

Gropman, Andrea; Shattuck, Kyle F.; Prust, Morgan J.; Seltzer, Rebecca R.; Breeden, Andrew L.; Hailu, Ayichew; Rigas, Amanda; Hussain, Rehan M.; VanMeter, John W.

doi:10.1002/hbm.21470

Cited by 26 publications

(31 citation statements)

References 24 publications

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“…We hypothesize that asymptomatic participants only demonstrate cognitive deficits in executive function and motor tasks when challenged. This has also been observed in fMRI studies evoking working memory task of increasing difficulty 19 .…”

Section: Discussionsupporting

confidence: 66%

“…Recently, more targeted studies have evaluated the extent of the neurological damage caused by hyperammonemic episodes and the regions of the brain that are most sensitive to these effects 19 . Our recent imaging study found that white matter in the frontal lobe is predominantly affected during hyperammonemic episodes in OTCD patients 21 , adding to our understanding of executive dysfunction in OTCD patients.…”

Section: Discussionmentioning

confidence: 99%

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Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency

Sprouse¹,

King²,

Helman³

et al. 2014

Molecular Genetics and Metabolism

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Background Urea cycle disorders are caused by dysfunction in any of the six enzymes and two transport proteins involved in urea biosynthesis. Our study focuses on Ornithine Transcarbamylase deficiency (OTCD), an X-linked disorder that results in a dysfunctional mitochondrial enzyme, which prevents the synthesis of citrulline from carbamoyl phosphate and ornithine. This enzyme deficiency can lead to hyperammonemic episodes and severe cerebral edema. The objective of this study was to use a cognitive battery to expose the cognitive deficits in asymptomatic carriers of OTCD. Materials and Methods In total, 81 participants were recruited as part of a larger urea cycle disorder imaging consortium study. There were 25 symptomatic participants (18 female, 7 male, 25.6 years ± 12.72 years), 20 asymptomatic participants (20 female, 0 male, 37.6 years ± 15.19 years), and 36 healthy control participants (21 female, 15 male, 29.8 years ± 13.39 years). All participants gave informed consent to participate and were then given neurocognitive batteries with standard scores and T scores recorded. Results When stratified by symptomatic participant, asymptomatic carrier, and control, the results showed significant differences in measures of executive function (e.g. CTMT and Stroop) and motor ability (Purdue Assembly) between all groups tested. Simple attention, academic measures, language and non-verbal motor abilities showed no significant differences between asymptomatic carriers and control participants, however, there were significant differences between symptomatic and control participant performance in these measures. Conclusions In our study, asymptomatic carriers of OTCD showed no significant differences in cognitive function compared to control participants until they were cognitively challenged with fine motor tasks, measures of executive function, and measures of cognitive flexibility. This suggests that cognitive dysfunction is best measurable in asymptomatic carriers after they are cognitively challenged.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency

Sprouse¹,

King²,

Helman³

et al. 2014

Molecular Genetics and Metabolism

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“…Previous studies on OTCD populations found increased activation in frontal regions, including the ACC, relative to controls despite a lack of differences in task performance, suggesting a model of prefrontal inefficiency [49]. It is possible that this increased ACC activity is a mechanism employed to compensate for the poor connectivity between the ACC and other areas critical for executive functioning, such as the insula, IPL, and SFG, as demonstrated by the current study.…”

Section: Discussionsupporting

confidence: 59%

Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency

et al. 2015

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Background and PurposeOrnithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks—default mode and set-maintenance—between OTCD patients and healthy controls.MethodsSixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity.ResultsGroup comparisons revealed reduced functional connectivity in the default mode network (DMN) of OTCD patients, particularly between the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) node and bilateral inferior parietal lobule (IPL), as well as between the ACC/mPFC node and the posterior cingulate cortex (PCC) node. Patients also showed reduced connectivity in the set-maintenance network, especially between right anterior insula/frontal operculum (aI/fO) node and bilateral superior frontal gyrus (SFG), as well as between the right aI/fO and ACC and between the ACC and right SFG.ConclusionInternodal functional connectivity in the DMN and set-maintenance network is reduced in patients with partial OTCD compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain.

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“…In a task-related fMRI design, a subject is placed in the magnet and scanned while performing various types of cognitive or motor tasks. We used two working memory tasks, the color STROOP and N-back which we have previously described [30]. …”

Section: Imaging Toolsmentioning

confidence: 99%

“…In addition, we observed accessory activation of regions not seen in controls. The effects of cognitive inefficiency intensified in the 2 back conditions of the testing [30]. …”

Section: Lessons Learned From Seven Years Of Imaging Otcd and Relamentioning

confidence: 99%

Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013

Pacheco‐Colón

Fricke

VanMeter

et al. 2014

Molecular Genetics and Metabolism

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Our previous imaging research performed as part of a Urea Cycle Rare Disorders Consortium (UCRDC) grant, has identified specific biomarkers of neurologic injury in ornithine transcarbamylase deficiency, OTCD. While characterization of mutations can be achieved in most cases, this information does not necessarily predict the severity of the underlying neurological syndrome. The biochemical consequences of any mutation may be modified additionally by a large number of factors, including contributions of other enzymes and transport systems that mediate flux through the urea cycle, diet and other environmental factors. These factors likely vary from one patient to another, and they give rise to heterogeneity of clinical severity. Affected cognitive domains include non-verbal learning, fine motor processing, reaction time, visual memory, attention, and executive function. Deficits in these capacities may be seen in symptomatic patients, as well as asymptomatic carriers with normal IQ and correlate with variances in brain structure and function in these patients. Using neuroimaging we can identify biomarkers that reflect the downstream impact of UCDs on cognition. This manuscript is a summary of the presentation from the 4th International Consortium on Urea cycle disorders held in, Barcelona, Spain, September 2, 2014.

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Altered neural activation in ornithine transcarbamylase deficiency during executive cognition: An fMRI study

Cited by 26 publications

References 24 publications

Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency

Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency

Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency

Advances in urea cycle neuroimaging: Proceedings from the 4th International Symposium on urea cycle disorders, Barcelona, Spain, September 2013

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